Fundamentals of Medicinal Chemistry

Vancomycin

O

O O

Cl

HOCH 2

R 2 O

H

NH

H NH−COCHNHCOCHNHCOCHNHCOCHNHCOCH

CHOH NHCH 3

CH 2 CH(CH 3 ) 2

HO

OH OH

H HOOC

O

CH 2 CONH 2

O

R 1 OH

HO

Cl

S

N O

HO CH 3 CH 3

H COOH

O

N O

O CH 2 OH

H

H COOH

Clavulanic acid

Sulbactam

Figure 7.2 (a)b-Lactamase inhibitors and (b) theb-lactamase resistant drug vancomycin

theb-lactam ring before the drug reaches the bacteria. However, with Gram-

negative bacteria, the hydrolysis takes place within the periplasmic space. In

addition, some Gram-negative bacteria produceacylases, which can cleave the

side chains of penicillins. Bacteria that have developed a resistance tob-lactam

antibiotics are treated using either a dosage form incorporating ab-lactamase

inhibitor, such as clavulanic acid or sulbactam, or a lactamase resistant drug,

such as vancomycin (Figure 7.2).

7.3 Drugs that target enzymes

Enzymes (Appendix 7) are often targets in drug design. Inhibition offers a

method of either preventing or regulating the chemical reactions occuring in

pathological conditions. Selecting a lead for an enzyme target requires either a

detailed knowledge of the biochemistry of the pathological condition or using

techniques such as computational (Chapter 5) and combinatorial chemistry

(Chapter 6). One advantage of targeting enzymes is that an enzyme process

that occurs in a pathogen may not occur in humans. This means that an

inhibitor active in a pathogen should not inhibit the same process in humans.

Enzyme inhibitors (I) may have either a reversible or irreversible action.

Reversible inhibitors tend to bind to an enzyme (E) by electrostatic bonds,

hydrogen bonds and van der Waals’ forces, and so tend to form an equilibrium

system with the enzyme. A few reversible inhibitors bind by weak covalent

bonds, but this is the exception rather than the rule. Irreversible inhibitors

138 SELECTED EXAMPLES OF DRUG ACTION AT SOME COMMON TARGET AREAS